外源性生长激素释放肽通过调节腺苷酸活化蛋白激酶通路改善大鼠心脏功能

Effects of Exogenous Ghrelin Through Regulation of AMP-Activated Protein Kinase Pathway Improves Cardiac Function in Rats

目的探索生长激素释放肽(Ghrelin)的心脏保护效应机制,明确外源性Ghrelin是否通过调节腺苷酸活化蛋白激酶(AMPKα2)及葡萄糖转运蛋白4(Glut4)表达而改善自发性糖尿病大鼠(GK)心脏功能。方法 GK大鼠编号随机分为3组:GK组、二甲双胍组(二甲双胍灌胃4周)和Ghrelin组(外源性Ghrelin腹腔注射4周),另选Wistar大鼠为对照。通过透射电镜观察大鼠心肌超微结构;应用多道生理记录仪观察大鼠心脏功能;留取大鼠动脉血液计算胰岛素抵抗指数(HOMA-IR);采用RT-PCR法测量AMPKα2及Glut4基因表达。结果实验4周后,与Wistar组及GK组比较,Ghrelin组心率降低,舒张、收缩功能改善(P<0.05);Ghrelin组大鼠的HOMA-IR指数低于GK组(P<0.05);Ghrelin组大鼠心肌内线粒体及心肌间微血管接近Wistar组;Ghrelin及二甲双胍干预后大鼠心肌AMPKα2和Glut4 mRNA表达量有明显增加(P<0.05)。结论 Ghrelin腹腔注射可减轻自发性糖尿病大鼠胰岛素抵抗,提高自发性糖尿病大鼠心脏左心室舒张和收缩功能,其机制可能与较长期在体上调心肌细胞AMPK表达而促进葡萄糖转运有关。

Aim To observe the role of Ghrelin on myocardial metabolism key enzyme AMP-activated protein kinase （AMPK） signaling pathway. Methods Goto-Kakizaki （GK） rats （8-week-old males） were randomly divided into three groups with 8 rats in each group： GK group, metformin group（ received metformin 350 mg/kg）, and Ghrelin group （received Ghrelin 200 μg/kg in twice daily）. Normal male Wistar kyoto rats （n =8） served as normal controls. Four weeks later, the effects of Ghrelin on cardiac remodeling were evaluated by echocardiographic, hemody- namicand gene expression analysis （AMPK, Glut4 mRNA expression）. Results After 4 weeks, compared with Wistar rats and GK group, heart rate reduced, diastolic, systolic function improved in Ghrelin group （P 〈 0. 05 ） ; HOMA-IR index was lower than the GK rats in Ghrelin group （P 〈 0. 05 ） ; Myocardial mitochondria and myocardial microvascular of Ghrelin group rats were close to Wistar group. Myocardial AMPKα2 , Glut4 mRNA expression levels were significantly increased in Ghrelin group compared with GK group （ P 〈 0. 05 ）. Conclusions Intraperitoneal injection of Ghrelin can reduce the spontaneous GK rats insulin resistance, and improve left ventricular diastolic and systolic function. Its mechanism may be associated with longer-term increase of AMPK expression of myocardial cell and the promotion of the glucose transporter.